Until a few years ago, the warfarin dose was altered based on the ratio of the patient's prothrombin time (PT) relative to the (normal) PT of a control preparation. However, the PTs tended to vary depending on the source of the reagents used in the lab.

It is now widely accepted that the anticoagulation level and the appropriate warfarin regimen are best determined on the basis of the international normalized ratio (INR). The INR value depends on the sensitivity ratio of the thromboplastin reagent used in the laboratory relative to the International Reference Preparation (IRP), a sensitive thromboplastin prepared from human brain.

This standardization system was introduced by the World Health Organization (WHO) in 1983 to provide a common basis for the interpretation of the PT results independent of the sensivity of the laboratory thromboplastin reagent which tends to vary from one manufacturer to another. The INR is derived from calibrations of commercial thromboplastin reagents against the International Reference Preparation (IRP). The calibration yields a value called the International Sensitivity Index or ISI. The manufacturer provides the ISI value for each lot of thromboplastin reagent. The lower the ISI value the more sensitive is the thromboplastin preparation. For the three commercial rabbit brain thromboplastins currently used in the US and Canada, the ISI ranges from 1.3 to 2.8.

The INR is calculated as the observed PT ratio raised to ISI^th power as shown in this equation:


INR = (observed PT ratio)ISI

The "observed PT ratio" is the ratio of the patient's PT divided by "the control PT". The control PT is often a constant value for each laboratory and it is referred to as the lab's average normal PT. Here are some examples:

Patient's PT	Control PT	ISI	INR
19	12	1.3	1.82
20	12	1.8	2.51
15	12	2.8	1.87
23	12	2.4	4.77
For most indications, the recommended INR is 2 to 3. For prosthetic heart valves the INR should be maintained between 2.5 and 3.5

References

1. van den Besselaar AM. Standardization of the prothrombin time in oral anticoagulant control. Haemostasis. 1985;15(4):271-7.
2. Kirkwood TBL. Calibration of reference thromboplastins and standardization of the prothrombin time ratio. Thromb Haemost 1983;49:238-44
3. Poller L. Progress in standerdization in anticoagulant control. Hematol Rev 1987;1:225-41
4. Consenus Conference on Antithrombotic Therapy Chest 1995 108(4):
5. Hylek EM. Oral anticoagulants. Pharmacologic issues for use in the elderly. Clin Geriatr Med. 2001;17(1):1-13. van den Besselaar AM. Standardization of the prothrombin time in oral anticoagulant control. Haemostasis. 1985;15(4):271-7.
6. Gallus AS et al. Consensus guidelines for warfarin therapy. Recommendations from the Australasian Society of Thrombosis and Haemostasis. Med J Aust. 2000;172(12):600-5.
7. Adcock DM, Duff S. Enhanced standardization of the International Normalized Ratio through the use of plasma calibrants: a concise review. Blood Coagul Fibrinolysis. 2000;11(7):583-90.

    

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